By Ronald Baker, PhD

PEG Intron (PEG-Interferon alfa 2b 1.5 mcg/kg/wk) + ribavirin 800mg/d is effective and approved for treatment of patients (pts) with chronic hepatitis C virus (HCV) infection. The medications have side effects and frequently require dose reduction or discontinuation.

Data comparing PEG-IFN alfa 2b (1.0 mcg/kg/wk) monotherapy yield equivalent sustained response rates in comparison to PEG-IFN alfa 2b (1.5 mcg/kg/wk) monotherapy. Sustained response rates and tolerability of PEG-IFN alfa 2b (1.0 mcg/kg/wk) + ribavirin are unknown.

In this trial, researchers sought to determine the efficacy and tolerability of PEG-IFN alfa 2b (1.0 mcg/kg/wk vs 1.5 mcg/kg/wk) in combination with ribavirin.

The investigators speculated that lower dose PEG-IFN alfa 2b may be equally effective and better tolerated than the standard dose.

Pts with chronic HCV (+ HCV RNA) were evaluated within the context of a prospective, randomized, controlled, multi-center trial comparing low dose (LD) PEG-IFN alfa-2b (1.0 mcg/kg/wk) + ribavirin (800-1400mg/d) vs. standard dose (SD) PEG-IFN alfa-2b (1.5 mcg/kg/wk) + ribavirin (800-1400mg/d).

Demographic, serological (ALT), virological (HCV RNA level and HCV genotype) and histological data were obtained. Eligible patients were randomized to one treatment group.

Medications were administered for 24 wks (HCV genotype [GT] non-1) or 48 wks (HCV genotype[GT] 1). Tolerability (side effect profile and drop out rate) was determined. Preliminary 24-wk treatment response data are reported.

246 pts have been enrolled. 103 pts (54 in LD and 49 in the SD) have received the medications for at least 24 wks. 40/54 (74%) in LD are GT1 in comparison to 37/49 (76%) in SD. 22/54 (41%) in LD have F2-4 in comparison to 26/49 (53%) in SD. There are no significant differences between the groups at baseline.

36/54 (67%) in LD are HCV RNA - at wk 24 {23/40 (58%) GT 1 and 13/14 (93%)GT non-1} in comparison to 25/49 (51%) in SD {16/37 (43%) GT 1 and 9/12 (75%) GT non-1}. 13% in LD discontinued the regimen prior to wk 24 in comparison to 16% in SD.

There is a trend to fewer adverse events in LD (52) in comparison to SD (64).

There are no significant differences in 24-wk treatment response rates or medication discontinuation rates.

Conclusions:

1)       PEG-IFN alfa 2b (1.0 mcg/kg/wk) + ribavirin is equally as effective as PEG-IFN alfa 2b 1.5 mcg/kg/wk + ribavirin in regards to HCV RNA - at week 24. This is true in GT 1 and GT non-1 pts.

2)       Medication discontinuation rates were equal between the two groups.

3)       There is a trend to fewer adverse events in the LD group.

5-28-03

Reference
SL Flamm and others. PEG IFN alfa 2b 1.0 mcg/kg/wk + ribavirin is equally as effective as PEG IFN alfa 2b 1.5 mcg/kg/wk + ribavirin: Preliminary results from a prospective, randomized, controlled, multi-center trial. Abstract 212 (oral).  Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

 

In interferon (IFN) non-responders with chronic hepatitis C, retreatment with standard interferons combined with ribavirin showed sustained virologic response rates of 20-30%. Concerning the efficacy of antiviral retreatment in patients not responding to a previous treatment with standard interferons combined with ribavirin, only limited data with conflicting results are available.

Therefore, the aims of the present trial were to evaluate efficacy and safety of a retreatment with PEG-Intron (pegylated IFN-alfa-2b) plus ribavirin in 240 patients (162 males, 78 females, mean age 45.5 years) not responding to previous antiviral treatment with standard interferons combined with ribavirin.

Patients received PEG-Intron 100 microgram/week s.c. for 8 weeks followed by 50 microgram/week subcutaneous (s.c.) for 40 weeks in combination with ribavirin 800 mg/d for 48 weeks. Treatment was discontinued in patients with detectable serum HCV-RNA after treatment week 24.

A virologic end-of-treatment response was achieved in 25/240 (10.4%) patients while after a follow-up period of 24 weeks a sustained virologic response was observed in 15/240 (6.3%) patients.

Patients infected with HCV genotype non-1 were more likely to respond to antiviral retreatment than patients infected with HCV genotype 1 (6.8% vs. 17%).

The authors conclude, “Antiviral retreatment with pegylated interferon-alfa-2b plus ribavirin in this flat and low dose showed only a limited therapeutic efficacy in patients with chronic hepatitis C not responding to previous treatment with standard interferons and ribavirin.

“In these patients, virologic response rates may be improved by administering pegylated interferon alfa-2b and ribavirin bodyweight adapted or by the addition of other antiviral agents.

05/28/03

Reference
G Teuber and others. Retreatment with Pegylated Interferon-Alpha2b Plus Ribavirin in Patients with Chronic Hepatitis C Not Responding to a Previous Antiviral Treatment with Standard Interferons Combined with Ribavirin. Abstract T1216 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

By Brian Boyle, MD

While HCV treatment response rates have been improved with pegylated interferon + Rebetol (ribavirin) therapy, rates of sustained virologic response, especially in HCV genotype 1, remain less than desirable, in the 29-37% range.

Response rates to that therapy are even lower in patients who previously did not respond to standard interferon + Rebetol therapy, in the 11 to 36% range. Since several studies have shown improved response rates in genotype 1 and previous nonresponders when consensus interferon (CIFN) is used, in a study presented at Digestive Disease Week 2003, investigators evaluated the efficacy of different doses of CIFN induction therapy – either 9 microgram QD for 16 weeks or CIFN 27 microgram QD for 4 weeks, followed by 12 weeks of CIFN 18 microgram QD – which was followed by a CIFN + Rebetol combination treatment in patients who were nonresponders to pegylated interferon + Rebetol therapy.

The study enrolled 23 patients, all of whom had elevated ALT-values and were HCV viremia, 22 of whom were HCV genotype 1. Liver biopsies in these patients revealed that 7 had bridging fibrosis or cirrhosis.

After the initial 16 weeks of CIFN monotherapy, 36% and 50% of the patients achieved undetectable serum HCV-RNA in the low and high dose CIFN groups, respectively. After 24 weeks of CIFN + Rebetol therapy, a negative HCV RNA was observed in 49% and 57% of the low dose CIFN + Rebetol and high dose CIFN + Rebetol patients, respectively.

Adverse effects led to CIFN dose reduction in 2 patients and discontinuation in 1 patient.

The authors conclude, “CIFN daily dosing/induction therapy together with subsequent ribavirin combination therapy thus shows response rates in about half of previous peginterferon combination therapy non-responders. If these primary response rates translate into correspondingly strong sustained response rates, an effective treatment will be in place for this difficult-to-treat patient group.”

05/28/03

Reference
S Kaiser and others. Successful Retreatment of Peginterferon Nonresponder Patients With Chronic Hepatitis C With High Dose Consensus Interferon Induction Therapy. Abstract 214 (oral). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

By Ronald Baker, PhD

The goal of eradicating HCV in the large majority of HCV-infected patients has not yet been reached. The challenge to reach this goal is particularly difficult among those patients who have either failed therapy or relapsed.

In the current study, the researchers hypothesized that response rates in non responders and relapsers who undergo re-treatment with peginterferon alfa plus ribavirin will experience a significantly improved response when compared to those who undergo re-treatment with standard interferon alfa with or without ribavirin.

The investigators designed the current prospective study to determine the effectiveness and safety of treatment with PEG-Intron (peginterferon alfa-2b) and ribavirin in patients who failed prior therapy with standard interferon with or without ribavirin.

The investigators enrolled 439 patients in this multi-center study. The first 250 enrolled patients were treated with 1.5 mcg/kg of PEG-Intron sc q week, and ribavirin 800 mg po qd.

The remaining patients received 1.5 mg/kg of PEG-Intron and weight based ribavirin (800-1400mg). The intended duration of treatment is 48 weeks regardless of 24-week HCV RNA results.

192 patients have been treated for at least 48 weeks and SVR data at week 72 is available in 98 patients, all treated with 800mg ribavirin/d

Dose reduction was required in 22% of pts most commonly due to leukopenia and anemia. Depression or anxiety resulted in the permanent discontinuation of therapy in 8%.

1.8% of 439 patients experienced serious adverse events, including one person each with neutropenia/MRSA sepsis, optic neuritis with monocular blindness, perirectal abscess, cellulitis and multi-organ failure, cutaneous and pulmonary sarcoidosis, pneumonia, homicidal ideation, and suicide.

The researchers concluded the following:

(1)      Overall ETR was 46% and SVR was 33%;

(2)      SVR was significantly higher in genotype non-1 patients and those who failed previous monotherapy;

(3)      15% of G1 non responders to Rebetron achieved an SVR (16% Caucasian, 12% Black);

(4)      It is hoped that a weight based dose of ribavirin will be associated with lower relapse rates and improved sustained response rates particularly in G1 pts.

05/28/03

Reference
PJ Gaglio and others. Treatment With Pegylated Interferon Alpha 2B and Ribavirin Produces Significant Sustained Virologic Response Rates in HCV Infected Patients who Failed Prior Therapy. Abstract T1210 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL,

The objective of this study was to analyze the cost effectiveness of histologic staging to determine which HCV-infected prisoners to treat.

HCV-infected inmates at Louisiana State Penitentiary are evaluated per a treatment algorithim in which histologic stage determines treatment eligibility.

Patients with Stage 0 or Stage 1 fibrosis with a fibrosis index (stage of fibrosis/number of years infected) <0.1 are not treated.

Those with Stage 1 with fibrosis index > 0.1 or Stages 2, 3 or 4 (with compensated liver disease) are treated.

The cost of treating genotype 1 patients with interferon (pegylated and non) and ribavirin was analyzed.

501 patients were evaluated in the clinic. Liver biopsies were performed on 221 patients. After histological classification, 124 patients were treated with Intron A (interferon alfa-2b) and ribavirin. The actual cost (drug alone) per week of interferon alfa and ribavirin was $336 and the estimated cost of pegylated interferon and ribavirin (drug alone) was $397 per week.

The cost of treating these 124 patients using the biopsy model was $15,159 per patient for a total cost of $1,879,716.

In the non-biopsy model, 221 patients would have been treated at a cost of $12,659 per patient for a total cost of $2,797,706.

A further analysis was performed using pegylated interferon and ribavirin for genotype 1 patients, which revealed a total cost of $2,082,415 for the biopsy model at $16,826 per patient treated and $3,295,739 for the non-biopsy model at $14,389 per patient treated.

The authors conclude, “Management of HCV in the prison system is evolving. A protocol using liver biopsy to establish need for treatment balances cost and complies with current recommendations.

Costs

05/28/03

Reference
MJ Marino and others. Biopsy vs. Non-Biopsy: A Comparison of Cost of Treatment of a Biopsy vs. Non Biopsy Model in the Management of HCV Prisoners. Abstract T1256 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

By Brian Boyle, MD

Approximately 60% of the patients who are treated with Rebetron (standard interferon + ribavirin) fail to respond to that therapy. The re-treatment of this population, with more a more effective regimen, for example pegylated interferon + Rebetol (ribavirin) is primarily for the possibility of viral eradication, but even if that goal is not attained, secondary benefits may include biochemical or histological improvement.

In a study presented at Digestive Disease Week 2003, 193 patients who were virologic non-responders to Rebetron therapy were treated with PEG-Intron (pegylated Interferon Alpha-2b) + Rebetol and evaluated regarding histologic improvement with that therapy.  Of the enrolled patients, 160 were HCV genotype 1. After enrollment, the patients were randomized to receive either PEG-Intron 1.5 mcg/kg/week + Ribavirin 800 mg/day or PEG-Intron 1.0 mcg/kg/week + Ribavirin 1000-1200 mg/day for 48 weeks.

The investigators found that of 49 patients with paired liver biopsies after finishing 48 weeks of treatment, 17 (35%) were HCV RNA negative and 32 (65%) were HCV RNA positive. In these patients, the overall Histological Activity Index (HAI) improved after treatment from 5.91 to 4.47 and the fibrosis score improved from 2.65 to 2.22.

As shown in the table below, while the HAI significantly improved in both virologic responders and nonresponders, histologic improvement in fibrosis was significant only in patients who achieved an undetectable HCV RNA by the end of treatment.

The authors conclude, “Significant histologic improvement was only seen in patients who achieved viral clearance by week 48. Patients that were PCR positive at week 48 achieved significant improvement in hepatic inflammation but not in fibrosis. Combination of Peg-Intron and Ribavirin is very effective in improving histologic activity in patients who failed to clear HCV RNA.”

05/28/03

Referemce
K Selim and others. Histological Improvement in Patients with Pegylated Interferon Alpha-2b plus Ribavirin Who Were Previously Non-Responders to Rebetron. Abstract 217 (oral). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

Neutropenia Associated with HCV Therapy May Not Be Associated with Serious Adverse Events

By Brian Boyle, MD

Neutropenia is a common event in patients treated with pegylated interferon and ribavirin; however, the clinical importance of the neutropenia is uncertain.

In a study presented at Digestive Disease Week 2003 (DDW), investigators evaluated whether the neutropenia induced in patients treated with pegylated interferon and ribavirin led to any clinically serious adverse events, such as infections. 

The investigators obtained data regarding adverse events from the WIN-R Trial, a study that enrolled 4,243 patients and compared fixed (800mg) versus weight based (800-1400mg) daily dosing of Rebetol (ribavirin) in combination with PEG-Intron (pegylated interferon alfa-2b). The investigators reviewed the adverse event data collected throughout the 48 weeks of therapy.

The investigators found that 30 (0.7%) of the patients developed infectious serious adverse events while on the PEG-Intron + Rebetol therapy. The infections included 10 patients with pneumonia, 3 with urinary tract infections, 3 with cellulitis, 2 with upper respiratory tract infections, 4 with an abscess, and one each with cat scratch disease, salmonella colitis, furuncle, meningitis, appendicitis with perforation, tibial hardware infection, bacteremia, and invasive C. jejuni diarrhea.

Of these patients, 24 received antibiotics, 27 were hospitalized, and 7 required surgical intervention. One patient died of pneumonia.

Examining the absolute neutrophil counts, the investigators found that the ANC fell below 1000 at some point in 14 of 25 (56%) of the patients that developed a serious infection. Further, they found that overall mean nadir ANCs in patients with a serious adverse event  and all treated patients were not significantly different, 1198 and 1318, respectively (p=0.46).

Finally, the mean nadir ANC for the serious adverse event patients also did not significantly differ from that of the rest of the patients and the proportion of patients who developed an ANC <750 were similar in both groups (20%).

Based upon these data the authors conclude, “(1) Patients who develop serious infections while on combination therapy with pegylated interferon alfa-2b and ribavirin do not have significantly lower mean nadir ANCs. (2) Infectious [serious adverse events] generally did not occur at the time of nadir ANC. (3) Criteria and utility for dose reduction of peginterferon and the use of granulocyte stimulating factor to treat neutropenia require further assessment.”

05/28/03

Reference
F Ahmed and others. Clinical Significance of Pegylated Interferon Induced Neutropenia: Results from the WIN-R Trial. Abstract 213 (oral). Abstracts of Digestive Disease Week 2003. May 17-22.  Orlando, FL, USA.

Steatosis Influences the Early Virologic Response Rate in Patients with Chronic Hepatitis C

Early virological response (EVR) is defined as a fall in HCV RNA levels by > or = 2 log₁₀ units at 12 weeks of treatment. Failure to achieve EVR is highly predictive of eventual non-response, and may be used to design early stopping rules for chronic hepatitis C genotype-1 infected patients.

Steatosis may influence SVR rates in chronic hepatitis C patients. The aim of the current study was to assess whether the degree of steatosis prior to initiation of therapy has a negative impact on EVR rates.

Patients that received initial therapy for HCV with interferon (or peginterferon) and ribavirin at a single center were included in the study. Pre-treatment liver biopsy specimens were blindly evaluated for steatosis by recording a percentage of affected hepatocytes and thereafter assigning a categorical grade [grade 0 (0-2%), grade 1 (3-29%), grade 2 (30-59%), grade 3 (> or = 60%)].

 Baseline demographic information and fasting laboratory values were determined at the time of liver biopsy. HCV RNA levels were measured at baseline and week 12 of therapy. Covariate effects were assessed using stepwise logistic regression analysis with EVR as the outcome.

160 patients were included in the analysis of which 115/160 (72%) achieved an EVR. Genotype-1 (GT-1) patients that achieved EVR appeared more likely to have grade 0 steatosis than grades 1-3, compared to those that did not have an EVR (71% v. 42%; p=0.003). Similar differences were not observed in GT non-1 patients.

Age, GT-1 and fat percentage were selected as significant predictors of EVR in a stepwise analysis (see table). When controlling for effects such as fibrosis stage, gender, genotype and BMI, GT-1 (p=0.007) and fat percent (p=0.046) remained significant predictors of EVR.

Parameter estimates indicated that an increase in fat of 1% was associated with a 4.7% decline in predicted odds of an EVR (for fat percentages from 0 to 25%). As expected, HCV GT non-1 patients had a 7 fold greater EVR rate compared to GT-1 patients.

Conclusions: According to the authors, “Increased steatosis is an independent variable that may reduce the likelihood of achieving EVR with combination therapy in chronic hepatitis C patients.

“Future prospective studies assessing EVR should also consider steatosis as an important factor that may influence treatment outcome.”

05/28/03

Reference
H M Patton and others. Steatosis Influences the Early Virologic Response Rate in Patients with Chronic Hepatitis C Infection. Abstract 232 (oral). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.